Process for the preparation of 3-fluorobenzodiazepines

ABSTRACT

3-Fluorobenzodiazepines, such as 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one, useful as tranquilizers, muscle relaxants, and sedatives.

This is a continuation of application Ser. No. 687,318, filed May 26,1976, which in turn is a continuation-in-part of Ser. No. 597,502, filedJuly 31, 1975, now abandoned.

BACKGROUND

This invention relates to benzodiazepine tranquilizers.

Bell, in U.S. Pat. No. 3,198,789, discloses 3-chloro derivatives ofbenzodiazepines as starting materials in the preparation ofbenzodiazepines with an amino group in the 3-position. He states thatthe chlorine at the 3-position is very reactive, the compounds reactingat room temperature or below; also that one skilled in the art oforganic chemistry would realize that the analogous 3-bromo and 3-iodocompounds could be used in place of the 3-chloro.

Bell, in U.S. Pat. No. 3,296,249, discloses a sequence of reactions thatincludes the preparation of3-halo-5-monocyclic-aryl-1,3-dihydro-2H-1,4-benzodiazepin-2-one from theunsubstituted N oxide. These are intermediates for making the 3-hydroxycompounds. The term halo is not defined. He also discloses that the3-hydroxy compounds can be converted to their corresponding 3-chloroderivatives by treating with an inorganic acid halide, such as thionylchloride or phosphorous pentachloride. Thionyl fluoride has beenunsuccessful as a fluorinating agent with alcohols. [Weichert, K. andHoffmeister, R., J. Prakt Chem., 10, 290-302 (1960)]

Bell et al., in U.S. Pat. No. 3,296,251, disclose 3-halo-benzodiazepinesas intermediates for preparing 3-mercapto-benzodiazepines, and statesthat a halogen at position 3 is very active: reacting at roomtemperature with mercapto compounds.

Fryer et al., in U.S. Pat. No. 3,371,083 disclose benzodiazepinessubstituted in the 3-position with chlorine, bromine, or iodine, whichare useful as intermediates.

Fryer et al., in U.S. Pat. No. 3,371,084 disclose3-halo-1,4-benzodiazepin-2-ones useful as intermediates, where thehalogen is preferentially bromine, chlorine, or iodine. Fluorine is notdisclosed.

Sternbach, in U.S. Pat. No. 3,450,695, discloses 3-halo-benzodiazepinesas intermediates made by treatment of the 3-hydroxy compound with ahalogenating agent, such as an inorganic acid halide.

Sternbach et al., in J. Med. Chem., 8, 815 (1965), describe thepreparation and some of the reactions of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one.

Bell and Childress, in J. Org. Chem., 27, 1691 (1962), disclose3,7-dichloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one prepared byreacting the 3-hydroxy compound with thionyl chloride. This 3-chloroderivative, however, was described as extremely reactive: mere warmingin alcohol caused decomposition.

Stempel et al., in U.S. Pat. No. 3,321,467, disclose3-halo-1,4-benzodiazepin-2-one 4-oxides prepared by treating2-halo-quinazoline 3-oxides with a suitable inorganic base. The halogenis defined as chlorine, bromine, or fluorine; preferably chlorine. Thefluorine derivative is not specifically described or exemplified.

No known reference discloses the 3-fluorobenzodiazepines of thisinvention. Several references teach 3-halo derivatives; mentioningchlorine, bromine, and iodine and specifically exemplifying chlorine.The consensus of the prior art is that 3-halo-benzodiazepines are tooreactive and unstable to be practically useful as pharmaceuticals.

There are fundamental differences, however, between chlorine, bromine,and iodine -- the halogens disclosed in the prior art -- and fluorine.It is known in organic chemistry that fluorine is a separate anddistinct entity in comparison to chlorine, bromine, and iodine; and isdifferent to such a degree that fluorocarbon chemistry has achieved acompletely separate status. Differences between these elements are many.For example:

Fluorine has no low-lying d-orbitals for backbonding as do chlorine,bromine, and iodine, thus leading to less polarizable bonds.

Chlorine, bromine, and iodine can be found in positive valence states(ClO₄, BrO₃, and I₂ O₅) whereas fluorine cannot.

The well-known "haloform" reaction occurs with bromine, chlorine, andiodine, but not with fluorine.

Metal-fluorides differ from metal-chlorides, -bromides, and -iodides:for example, the solubility of silver fluoride in water is one milliontimes greater than the solubility of silver-chloride, -bromide, and-iodide.

Many authorities have noted and recognized the differences betweenfluorine and halogens. For example:

Sheppard and Sharts, in "Organic Chemistry", W. A. Benjamin (1969)devote the first two chapters to the differences between fluorine andthe halogens.

Cotton and Wilkinson, in "Advanced Inorganic Chemistry", Interscience(1962) discuss fluorine compounds in Chapter 14, and chlorine, bromine,and iodine compounds in Chapter 22.

Roberts and Caserio in "Basic Principles of Organic Chemistry", W. A.Benjamin (1964) in Chapter 17, covers chlorine, bromine, and iodinecompounds under headings "Alkyl Halides", "Alkenyl Halides", "CycloalkylHalides", and "Polyhalogen Compounds". Fluorine compounds are coveredunder "Fluorinated Alkanes."

Accordingly, under modern chemical practice, fluorine has acquired aseparate status, and therefore it is incorrect to conclude that mentionof the halogens chlorine, bromine, or iodine necessarily suggestsfluorine.

In marked contrast to the 3-chloro-benzodiazepines of the prior art,which Bell and Childress said were too unstable to even givesatisfactory analytical results, the 3-fluoro-benzodiazepines of thisinvention are surprisingly stable against hydrolysis by both aqueousacids and bases, making them especially suitable as pharmaceuticals.

A number of benzodiazepines are well-known useful tranquilizers,muscle-relaxants, and sedatives. Metabolic studies with several of thesecompounds, including diazepam [Schwartz, M. A. et al., J. Pharmacol.Exp. Ther., 149, 423 (1965)], flurazepam [Schwartz, M. A. and Postma, E.J Pharm. Sci., 59, 1800 (1970)], and nitrazepam [Rieder, J. and Wendt,G., "Benzodiazepines", Garattini, S., Mussini, E., and Randall, L. O.,eds., 799, Raven Press, New York (1973)], have shown that they aremetabolized in man and other animals by oxidative attack at the3-position. Substitution with fluorine in this 3-position appears toretard this metabolic pathway, resulting in more potent activity for the3-fluoro derivatives of this invention.

SUMMARY

According to this invention there is provided compounds of formula I,processes for making them, pharmaceutical compositions containing them,and methods of using them as tranquilizers, muscle-relaxants, andsedatives in mammals. ##STR1## where X is Cl, Br, NO₂ or CF₃ ;

Y is H, Cl, Br or F;

Z = h, hydrocarbyl of 1-4 carbons, --CH₂ CF₃, --CONHR, --CH₂ CH₂ NR₂, or--CH₂ CH₂ NR₂.A, where R = alkyl of 1-4 carbons, and A is apharmaceutically suitable acid;

B = o; or

B and Z together = ═N--N═C(R')-- where R' = H, or C₁ -C₄ alkyl.

DETAILED DESCRIPTION Preferred Compounds

Compounds preferred for their activity are those where, independently:

B = o;

x = cl;

Z = h;

z = c₁ -c₃ alkyl;

X = cl and Z = H;

X = cl and Z = C₁ -C₃ alkyl.

More preferred are those compounds where:

X = cl or Br;

Y = h, cl, or F;

Z = h, --ch₃, or --CH₂ CH₃ ; and

B = o.

most preferred are those compounds where:

X = cl or Br;

Y = h or F;

Z = ch₃ ; and

B = o.

specifically preferred are the following compounds:

3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one;

3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-(2'-fluorophenyl)-2H-1,4-benzodiazepin-2-one;

3-fluoro-1,3-dihydro-1-methyl-7-bromo-5-phenyl-2H-1,4-benzodiazepin-2-one;

3-fluoro-1,3-dihydro-7-bromo-5-phenyl-2H-1,4-benzodiazepine-2-one.

The term hydrocarbyl of 1-4 carbons includes alkyl groups such asmethyl, ethyl, isopropyl, and isobutyl; cycloalkyl containing groupssuch as cyclopropyl and cyclopropylmethyl; and alkenyl groups such asallyl and 2-butenyl.

Pharmaceutically suitable acids (A) include those such as HCl, H₂ SO₄,HNO₃, H₃ PO₄, acetic, tartaric, citric, maleic, fumaric, and the like.

Synthesis

These compounds are made by the following general method: Contacting a3-hydroxybenzodiazepine with a dialkylaminosulfur trifluoride at about-80° to 10° C. under substantically anhydrous conditions: ##STR2##

B, X, Y and Z are as previously defined. R¹ and R² individually are aprimary alkyl group of 1-4 carbons or taken together are --(CH₂)₄ -- or--(CH₂)₅ --.

It is preferred to operate in the temperature range of -80° to -10° C.when Z is hydrogen; and -80° to +10° C. when Z is other than hydrogen.

The dialkylaminosulfur trifluorides decompose very readily on contactwith water, so water should be excluded from the reaction as much aspossible. "Substantially anhydrous conditions" is therefore intended tomean that the amount of water present is so small that it will notsignificantly decompose the dialkylaminosulfur trifluoride,consequently, not interfering with the reaction.

The reaction can be carried out by dissolving or suspending the hydroxylcompound in an inert solvent and then adding the fluorinating agent. Aninert solvent is one that does not enter into the reaction and includesdiethyleneglycol dimethyl ether (diglyme), pentane,trichlorofluoromethane, and the like; preferred are chlorinated solventsthat are liquid at the reaction temperature, such as methylene chlorideand chloroform. The product can be isolated from the reaction mixtureand purified by conventional means; for example, the reaction mixturecan be poured into water, the organic layer separated and washed withwater, and then evaporated to dryness. The resulting crude3-fluorobenzodiazepines can then be further purified byrecrystallization from suitable solvents.

The 3-hydroxy-benzodiazepines used in this reaction are either knowncompounds or can be prepared by methods described in the literature. Forexample: Bell and Childress, J. Org. Chem., 27, 1691 (1962); Bell etal., Tetrahedron Lett., p. 2889 (1965); Bell et al., J. Org. Chem., 33,216 (1965); Miyadera et al., J. Med. Chem., 14, 520 (1971); Ning et al.,J. Org. Chem., 38, 4206 (1973); Sankyo Company, German Pat. No.1,812,252 (1969); 1,952,201 (1970); 1,954,065 (1970); Schlager,Tetrahedron Lett., p. 4519 (1970); Stempel et al., J. Org. Chem., 32,4267 (1967); Stempel et al., J. Org. Chem., 30, 4267 (1965).

The dialkylaminosulfur trifluorides can be prepared by the reaction of adialkylaminotrimethylsilane with sulfur tetrafluoride at a lowtemperature in an inert solvent. Diethylaminosulfur trifluoride,dimethylaminosulfur trifluoride, and pyrrolidinosulfur trifluoride canbe prepared by this method. When this reaction is conducted intrichlorofluoromethane at -70° C., high yields of a product of highpurity are obtained because the only appreciable by-product isfluorotrimethylsilane, an easily separated low boiling material. Thesethree trifluorides are stable products that can be distilled and storedin plastic bottles at room temperature.

Preparation and use of these fluorinating agents is described byMiddleton, W. J., J. Org. Chem., 40, 574 (1975) and U.S. Pat. No.3,914,265 issued Oct. 21 1975.

DIETHYLAMINOSULFUR TRIFLUORIDE

    (C.sub.2 H.sub.5).sub.2 N --Si(CH.sub.3).sub.3 + SF.sub.4 → (C.sub.2 H.sub.5).sub.2 NSF.sub.3 + FSi(CH.sub.3).sub.3

a dry 1-l. four-necked round-bottomed flask is equipped with athermometer (-100° to 50°), a solid carbon dioxide-cooled refluxcondenser (protected from the atmosphere through a drying tube), a gasinlet tube above the liquid level, and a magnetic stirrer. The apparatusis flushed with dry nitrogen, and 300 ml of trichlorofluoromethane isadded to the flask. As the nitrogen atmosphere is maintained, thetrichlorofluoromethane is cooled to -70° by means of a solid carbondioxide-acetone bath and 119 g (1.1 mole) of sulfur tetrafluoride isadded from a cylinder through the gas inlet tube. The gas inlet tube isthen replaced with a 250-ml pressure-equalized dropping funnel chargedwith a solution of 145 g (1 mole) of N,N-diethylaminotrimethylsilane in90 ml trichlorofluoromethane. This solution is added dropwise, withstirring, to the sulfur tetrafluoride solution at a rate slow enough tokeep the temperature of the reaction mixture below -60° (about 40minutes). The cooling bath is removed, and the reaction mixture isallowed to warm spontaneously to room temperature. The condenser isreplaced with a simple distillation head, and the solvent (bp 24°) andby-product fluorotrimethylsilane (bp 17°) are distilled off into a wellcooled receiver by warming the reaction mixture gently to 45° by meansof a heating mantle. The yellow to dark brown residual liquid istransferred and distilled at reduced pressure through a spinning bandcolumn to give 129-145 g (80-90%) of diethylaminosulfur trifluoride as alight yellow liquid, bp 46-47 (10 mm).

An alternate method for making benzodiazepinones where Z is other thanhydrogen is contacting a 3-fluorobenzodiazepinone with sodium hydride atabout 0°-30° C. in an inert solvent such as tetrahydrofuran,1,2-dimethoxymethylene, or diethylether, to produce the sodium salt;then contacting this, in the same solvent without isolation, with analkylating agent to produce a 1-alkyl-3-fluorobenzodiazepinone. Thealkylating agent can have the formula QZ¹ where Z¹ has the same value aspreviously defined for Z but excludes hydrogen; and Q is I, Cl, Br, CF₃SO₂ O--, FSO₂ O--, CCl₃ SO₂ O--, or Z¹ OSO₂ O--.

4-Fluorotriazolobenzodiazepines, such as4-fluoro-8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4.3-a][1,4]-benzodiazepinefor example, can be prepared as follows: by treating a solution of8-chloro-4-hydroxy-1-methyl-4H-s-triazolo[4.3-a][1,4]benzodiazepine inmethylene chloride with diethylaminosulfur trifluoride at -70°, warmingthe reaction mixture to -20°, and then pouring it into cold water.4-Fluoro-8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4.3-a][1,4]benzodiazepinecan be isolated from the organic layer by evaporation of the solvent.The particular 4-hydroxy compound shown here can be prepared asdescribed in U.S. Pat. No. 3,907,820 (1975) (assigned to Takeda ChemicalIndustries, Ltd.).

The following examples further illustrate how to make the compounds ofthis invention. Parts are by weight and temperatures are in degreesCentigrade unless otherwise specified.

EXAMPLE 13-Fluoro-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one##STR4##

A well stirred suspension of 10 g (0.03 mol) of3-hydroxy-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one and500 ml of methylene chloride was cooled to -70°. Diethylaminosulfurtrifluoride (25 ml, 0.2 mol) was then added dropwise with exclusion ofmoisture and air. On completion of the addition the dry-ice acetone bathwas removed, the contents of the flask were allowed to warm up in about25 minutes to -10° and the reaction then immediately quenched by pouringinto a beaker containing 400-500 ml of ice water. (If the reactionmixture is allowed to warm to 25°, none of the desired product isobtained.) Vigorous stirring of the ice water mixture continued for 7 to10 minutes. The organic layer was separated, dried over MgSO₄ andevaporated under reduced pressure to give a light orange powder. Theproduct was dissolved in hot benzene, treated with decolorizing charcoaland filtered hot. On addition of heptane to the benzene solution,followed by cooling in ice,3-fluoro-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-onecrystallized out as a white powder, 8.19 g (82%): mp 190°-192° (decom.);¹⁹ F nmr (DMSO-d₆) δ -161.5 ppm (d, d, J = 56, 4 Hz, 1H), ¹ H nmr(DMSO-d₆) δ 7.2-7.8 (m, 8H), δ 5.72 (d, J = 56 Hz, 1H), δ 11.0 ppm(N-H).

    ______________________________________                                        Anal. Calcd for C.sub.15 H.sub.10 ClN.sub.2 OF:                                                 C,    62.40;  H,  3.49;                                                                              N, 9.70                              Found:            C,    62.77;  H,  3.97;                                                                              N, 9.29                                                      62.72       4.01   9.31                               ______________________________________                                    

EXAMPLE 23-Fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one##STR5##

A. A solution of 12.1 g (0.04 mol) of3-hydroxy-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-onein 25 ml of anhydrous methylene chloride was added dropwise over aperiod of 15 min. to a stirred solution of 12.6 ml (0.1 mol) ofdiethylaminosulfur trifluoride in 300 ml of anhydrous methylene chloridecooled to -70°. The reaction mixture was allowed to warm slowly over aperiod of 45 min. to 5° and then poured into 500 ml of ice and water.The lower organic layer was separated, washed with water, dried overanhydrous magnesium sulfate, and evaporated to dryness under reducedpressure to give 10.9 g (90% yield) of crude product as a light yellowsolid residue. Recrystallization from heptane gave 8.48 g (70% yield) of3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-oneas colorless crystals: mp 138°-140°; ¹⁹ F nmr (CCl₃ D) δ -161.7 ppm (d,J = 57 Hz); ¹ H nmr (CCl₃ D) δ 3.43 ppm (s, 3H), 5.54 ppm (d, J = 57 Hz,1H), 7.5 ppm (m, 8H).

Anal. Calcd for C₁₆ H₁₂ ClFN₂ O: C, 63.47; H, 4.00; F, 6.28; N, 11.71.Found: C, 63.53; H, 4.21; F, 6.21; N, 11.50.

B. The same compound can be prepared by the alternate method as follows:##STR6##

To a well stirred solution of 3.0 g (0.01 mol) of3-fluoro-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one, 75 mlof dry THF and 25.56 g (0.18 mol, 11.2 ml) of methyl iodide was added asuspension of 0.48 g (0.02 mol) of sodium hydride in 20 ml of THF. Therewas an immediate evolution of hydrogen. The contents of the flask werestirred under a nitrogen atmosphere for exactly 2 hours. The productmixture was poured into approximately 100 ml of water and methylenechloride added to extract the product. The organic layer was separatedand washed twice with ca. 50 ml portion of fresh water, and then allowedto dry over magnesium sulfate. Evaporation of the solvent under reducedpressure gave 1.38 g of a yellow crystalline material. Recrystallizationfrom hot heptane gave 0.97 g of an off-white powder identified as3-fluoro-1-(N-methyl)-7-chloro-5-phenyl-1,4-benzodiazepin-2-one: ¹ H nmr(DMSO-d₆): δ 7.2-7.72 ppm (m, 8H), δ 5.8 ppm (d, 1H, 56 Hz), δ 3.37 (m,3H, N-methyl); ¹⁹ F nmr (DMSO-d₆) δ -160.14 ppm (d, J = 56 Hz).

EXAMPLE 33-Fluoro-1,3-dihydro-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one##STR7##

A well stirred suspension of 3.0 g (0.01 mole) of3-hydroxy-1,3-dihydro-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-onein 150 ml of methylene chloride was cooled to -70°, and 7.5 ml (0.06mol) of diethylaminosulfur trifluoride was added dropwise over a periodof 10 min. The reaction mixture was then allowed to warm slowly over aperiod of 26 min. to -10° and then poured into 200 ml of ice water. Theorganic layer was separated, dried over MgSO₄, and evaporated to drynessunder reduced pressure to give 2.95 g (98%) of crude product.Recrystallization from benzene-heptane gave 2.00 g (67%) of3-fluoro-1,3-dihydro-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneas off-white crystals: mp 206°-207° (dec); ¹ H nmr (DMSO-d₆) δ 5.95 ppm(d, J = 56 Hz, 1H), 7.47 ppm (m, 7H), 11.25 ppm (s, 1H); ¹⁹ F nmr(DMSO-d₆) δ -162.0 ppm (d, J = 56 Hz, 1F) and δ -113.0 ppm (m, 1F).

Anal. Calcd for C₁₅ H₉ ClF₂ N₂ O: C, 58.74; H, 2.96; F, 12.39; N, 9.14.Found: C, 58.54; H, 3.21; F, 12.11; N, 8.98.

EXAMPLE 43Fluoro-1,3-dihydro-1-ethyl-7-chloro-5-phenyl-2H,-1,4-benzodiazepin-2-one##STR8##

A solution of 3.5 g (0.01 mol) of3-hydroxy-1,3-dihydro-1-ethyl-7-chloro-5-phenol-2H-1,4-benzodiazepin-2-onein 7 ml of anhydrous methylene chloride was added dropwise to a stirredsolution of 3.53 ml (0.028 mol) of diethylaminosulfur trifluoride in 84ml of anhydrous methylene chloride cooled to -70°. The reaction mixturewas allowed to warm slowly to 5° and then poured into 150 ml of ice andwater. The lower organic layer was separated, washed with water, driedover anhydrous magnesium sulfate, and evaporated to dryness underreduced pressure to give 2.84 g (90% yield) of crude product as lightyellow crystals. Recrystallization from 200 ml of heptane gave 1.81 g(57% yield) of3-fluoro-1,3-dihydro-1-ethyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one:mp 156°-158°; ¹ H nmr (DMSO-d₆) δ 7.2-7.8 ppm (m, 8H), δ 5.85 ppm (d,1H, J = 57 Hz), δ 3.5-4.38 (m, 2H, methylene protons on nitrogen), δ1.02 (t, 3H).

Anal. Calcd for C₁₇ H₁₄ N₂ ClF: C, 64.46; H, 4.46; F, 6.00; N, 8.84.Found: C, 64.46; H, 4.71; F, 6.57; N, 8.67.

EXAMPLE 53-Fluoro-1,3-dihydro-1-methyl-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one##STR9##

A solution of 1.4 g of3-hydroxy-1,3-dihydro-1-methyl-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-onein 10 ml of methylene chloride was added dropwise to a stirred solutionof 1.5 ml of diethylaminosulfur trifluoride in 50 ml methylene chloridecooled to -70°. The reaction mixture was allowed to warm slowly to 5°and then poured into 100 ml of ice water. The lower organic layer wasseparated, washed with water, dried over anhydrous magnesium sulfate,and evaporated to dryness under reduced pressure. The residue wasrecrystallized from heptane to give 1.17 g of3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneas cream-colored crystals: mp 91°-95°; Hu 1H nmr (CCl₃ D) δ 3.51 ppm (s,3H), 5.66 ppm (d, J = 57 Hz, 1H) and 7.5 ppm (m, 7H).

Anal. Calcd for C₁₆ H₁₁ ClF₂ N₂ O₂ : C, 59.91; H, 3.46; F, 11.85; N,8.74. Found: C, 60.00; H. 3.57; F, 11.55; N, 8.69.

EXAMPLE 63-Fluoro-1-(allyl)-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one##STR10##

To a well stirred solution of 3.0 g (0.01 mol) of3-fluoro-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one, 75 mlof dry THF and 21.78 g (0.18 mol) of 3-bromopropene, was added asuspension of 0.48 g (0.02 mol) of sodium hydride in 20 ml of THF. Therewas an immediate evolution of hydrogen. The contents of the flask werestirred under a nitrogen atmosphere for exactly two hours. The productmixture was poured into 100 ml of water and methylene chloride was addedto extract the product. The organic layer was washed twice with 50 mlportions of water, and then allowed to dry over magnesium sulfate.Evaporation of the solvent under reduced pressure gave an orange glueymaterial which was recrystallized from 450 ml of hot heptane to give1.42 g of3-fluoro-1-(allyl)-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one as avery pale orange powder: mp 138°-140°, ¹ H nmr (CDCl₃) δ 7.2-7.9 ppm (m,8H), δ 5.6 ppm (d, J = 57.5 Hz, 1H), δ 4.85-5.95 ppm (m, 3H, olefinic),δ 4.58 ppm (2H, N--CH₂); ¹⁹ F nmr (CDCl₃) δ 161.97 ppm.

Anal. Calcd for C₁₈ H₁₄ N₂ ClF: C, 65.76; H, 4.29; F, 5.78; N, 8.52.Found: C, 66.06; H, 4.55; F, 5.46; N, 8.29.

EXAMPLE 73-Fluoro-7-bromo-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one##STR11##

A well stirred suspension of 6.0 g (0.018 mole) of7-bromo-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one in 250ml methylene chloride was cooled to -70°, and 7.5 ml (0.06 mole) ofdiethylaminosulfur trifluoride was added dropwise. The reaction mixturewas allowed to warm slowly to -10° over a period of 30 min., and held at-10° for 20 min., until most of the solid had dissolved. The reactionmixture was poured into 500 ml of ice water and stirred until the yellowcolor faded. The organic layer was separated, dried over MgSO₄, andevaporated to dryness under reduced pressure. The residue was dissolvedin 300 ml of hot benzene and filtered hot. The filtrate was mixed with400 ml hexane and cooled. The crystals that separated were collected ona filter, washed with hexane, and dried in air to give 5.28 g (88%) of3-fluoro-7-bromo-1,3-dihydro- 5-phenyl-2H-1,4-benzodiazepin-2-one ascolorless crystals: mp 207°-209° (dec.); ¹⁹ F nmr (acetone-d₆) δ -162.6ppm (d, J = 57 Hz); ¹ H nmr (acetone-d₆) δ 5.86 ppm (d, J = 57 Hz, 1H),7.2-8 ppm (m, 8H), 9.90 ppm (NH); ir (KBr) 5.84μ (C═O). A sample wasdried in a vacuum oven for analysis.

Anal. Calcd for C₁₅ H₁₀ BrFN₂ O: C, 54.07; H, 3.03; N, 8.41; F, 5.70.Found: C, 54.31; H, 3.17; N, 8.40; F, 5.62.

The 7-bromo-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-oneused in this preparation was prepared by the following procedure. A10.0-g (0.03 mole) sample of7-bromo-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide wasadded portionwise to 50 ml of trifluoroacetic anhydride, and thereaction mixture was stirred at room temperature for 2 hr. The suspendedsolid was collected on a filter, washed thoroughly with pentane, anddried in vacuum over potassium hydroxide pellets to give 12.8 g (99%) of7-bromo-1,3-dihydro-5-phenyl-3-trifluoroacetoxy-2H-1,4-benzodiazepin-2-oneas a white crystalline powder; mp 181°-183°; ¹ H nmr (DMSO-d₆) δ 6.28ppm (s, 1H), 7.64 ppm (m, 8H), and 11.38 ppm (NH); ¹⁹ F nmr (DMSO-d₆) δ-74.6 ppm (s).

Anal. Calcd for C₁₇ H₁₀ BrF₃ N₂ O₃ : C, 47.79; H, 2.36; N, 6.56. Found:C, 47.66; H, 2.33; N, 6.26.

A suspension of 10 g (0.023 mole) of7-bromo-1,3-dihydro-5-phenyl-3-trifluoroacetoxy-2H-1,4-benzodiazepin-2-onein a mixture of 130 ml ethanol and 130 ml of 5% aqueous sodiumbicarbonate was stirred at room temperature (25°) for 20 hr. Thesuspended solid was then collected on a filter, washed with water, andrecrystallized from ethanol to give 6.5 g (85%) of7-bromo-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one ascolorless plates: mp 190°-192°; ¹ H nmr (DMSO-d₆) δ 4.86 ppm (1H), 6.27ppm (1H, OH), 7.18-7.90 ppm (m, 8H).

Anal. Calcd for C₁₅ H₁₁ BrN₂ O₂ : C, 54.40; H, 3.35; N, 8.46. Found: C,54.61; H, 3.51; N, 8.47.

EXAMPLE 83-Fluoro-7-bromo-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one##STR12##

A slurry of 0.34 g (0.014 mole) of sodium hydride in 20 ml oftetrahydrofuran was added to a solution of 4.0 g (0.012 mole) of7-bromo-1,3-dihydro-3-fluoro-5-phenyl-2H-1,4-benzodiazepin-2-one and 13ml methyl iodide in 125 ml of tetrahydrofuran. The reaction mixture wasstirred for 2.5 hr at room temperature (25°) and then poured into 600 mlof water containing 200 ml of methylene chloride. The organic layer wasseparated, washed with water, dried (MgSO₄), and evaporated to drynessto give 3.4 g of yellow residue. Recrystallization from cyclohexane gave1.50 g of7-bromo-1,3dihydro-3-fluoro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneas an amorphous cream-colored solid (no distinct melting point): ¹ H nmr(CDCl₃) δ 3.46 ppm (s, 3H), 5.60 ppm (d, J = 57 Hz, 1H), 7.2-7.9 ppm (m,8H); ¹⁹ F nmr (CDCl₃) δ -161.7 ppm (d, J = 57 Hz).

Anal. Calcd for C₁₆ H₁₂ BrFN₂ O: C, 55.35; H, 3.49; F, 5.47. Found: C,55.62; H, 3.72; F, 5.30; N, 7.97.

EXAMPLE 93-Fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one##STR13##

A stirred suspension of 4.2 g (0.012 mole) of7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-onein 200 ml methylene chloride was cooled to -70°, and 5 ml (0.04 mole) ofdiethylaminosulfur trifluoride was added dropwise. The reaction mixturewas allowed to warm to -10°, and held at this temperature until most ofthe solid had dissolved. The reaction mixture was poured into ice-waterand stirred vigorously. The organic layer was separated, washed withwater, dried (MgSO₄) and evaporated to dryness under reduced pressure.The residue was recrystallized from benzene-hexane to give 3.12 g of3-fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-oneas light yellow crystals: mp 195°-197° (dec.); ¹⁹ F nmr (DMSO-d₆) δ-113.0 ppm (m, 1F) and -162.1 ppm (d, J = 56 Hz, 1F); ¹ H nmr (DMSO-d₆)δ 5.88 ppm (d, J = 56 Hz, 1H), 7.2-7.9 ppm (m, 7H), 11.2 ppm (NH).

Anal. Calcd for C₁₅ H₉ BrF₂ N₂ O: C, 51.30; H, 2.58; F, 10.81; N, 7.98.Found: C, 51.50; H, 2.69; F, 10.53; N, 8.05.

The7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-oneused in this preparation was prepared by the following procedure.

A 9.5-g (0.027 mole) portion of7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one4-oxide was added portion-wise to 50 ml of trifluoroacetic anhydride,and the reaction mixture was stirred for 90 minutes. The suspended solidthat formed was collected on a filter, washed thoroughly with pentaneand dried in a vacuum over KOH. There was obtained 9.72 g (80%) of7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-trifluoroacetoxy-2H-1,4-benzodiazepin-2oneas an off-white crystalline powder: mp 175°-177° (dec.); ¹⁹ F nmr(DMSO-d₆) δ -74.6 ppm (s, 3F) and -112.7 ppm (m, 1F); ¹ H nmr (DMSO-d₆)δ 6.34 ppm (s, 1H), 7.1-8.1 ppm (m, 7H), 11.5 ppm (NH).

Anal. Calcd for C₁₇ H₉ BrF₄ N₂ O₃ : C, 45.86; H, 2.04; F, 17.70; N,6.29. Found: C, 44.55; H, 1.91; F, 18.00; N, 6.31.

A suspension of 9.5 g (0.021 mole) of7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-trifluoroacetoxy-2H-1,4-benzodiazepin-2-onein a mixture of 130 ml ethanol and 130 ml aqueous 5% sodium bicarbonatewas stirred at 25° for 18 hr. The suspended solid was collected on afilter, washed with water, dried in air, and recrystallized from ethanolto give 4.54 g (62%)7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-oneas colorless crystals: mp 196°-198°; ¹⁹ F nmr (DMSO-d₆) δ -113.5 ppm(m); ¹ H nmr (DMSO-d₆) δ 4.88 ppm (s, 1H), 6.35 ppm (s, OH), 7.0-7.9 ppm(m, 7H).

Anal. Calcd for C₁₅ H₁₀ BrFN₂ O₂ : C, 51.59; H, 2.89; F, 5.44; N, 8.02.Found: C, 51.63; H, 2.97; F, 5.41; N, 7.89.

EXAMPLE 103-Fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one##STR14##

A slurry of 0.17 g (0.007 mole) of sodium hydride in 10 ml oftetrahydrofuran was added to a solution of 1.8 g (0.005 mole) of3-fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-oneand 10 ml methyl iodide in 100 ml tetrahydrofuran. The reaction mixturewas stirred for 3 hr at 25° and then poured into 300 ml ice water. Theaqueous mixture was extracted with methylene chloride, and the extractswere dried (MgSO₄) and then evaporated to dryness under reducedpressure. The residue was recrystallized from heptane to give 0.91 g(50%) of cream-colored crystals: mp 127°-130° (with previous softening);¹ H nmr (CDCl₃) δ 3.49 ppm (s, 3H), 5.62 ppm (d, J = 57 Hz, 1H) and6.9-7.9 ppm (m, 7H); ¹⁹ F nmr (CDCl₃) δ -111.9 ppm (m, 1F) and -162.4ppm (d, J = 57 Hz, 1F).

Anal. Calcd for C₁₆ H₁₁ BrF₂ N₂ O: C, 52.62; H, 3.04; F, 10.41; N, 7.67.Found: C, 52.49; H, 3.30; F, 10.31; N, 7.57.

EXAMPLE 113-Fluoro-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one##STR15##

A well-stirred suspension of 6.8 g (0.021 mol)8-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-onein 350 ml methylene chloride was cooled to -72° under nitrogen.Diethylaminosulfur trifluoride (10.5 ml, 0.80 mol) was added dropwiseover a period of 10 min. at -72° to -70°. The suspension was allowed towarm slowly to -10° and held at -10° for 30 min., then poured into 500ml ice water with vigorous stirring. The organic layer was separated,dried over MgSO₄ and evaporated, yielding 7.8 g of orange-yellow solid.The product was dissolved in benzene and allowed to crystallize,yielding 3.59 g of white crystalline8-chloro-5-(2-chlorophenyl)-3-fluoro-3H-1,4-benzodiazepin-5-one: mp210°-211° (dec.); 95% pure by high pressure liquid chromatography and UVanalysis. A second crop (1.7 g) was obtained by addition of n-hexane. ¹H nmr (DMSO-d₆) δ 11.3 ppm (m, 1H), δ 7.5 ppm (m, 6H), 7.03 ppm (d, 1H),δ 5.92 ppm (d, J = 56 Hz, 1H); ¹⁹ F nmr (DMSO-d₆) δ -162.3 ppm (d, J =56 Hz, to d, J = 4 Hz).

EXAMPLE 123-Fluoro-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one##STR16##

Sodium hydride (0.25 g of 50% mineral oil emulsion washed twice withtetrahydrofuran, 0.0050 mole) in 10 ml tetrahydrofuran was addedportionwise at ambient temperature to a well stirred solution of 1.7 g(0.0053 mole)3-fluoro-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-oneand 5.6 g (0.039 mole) methyl iodide in 50 ml tetrahydrofuran undernitrogen. The solution was stirred 2 hr at room temperature, then pouredinto 100 ml water. The product was extracted with methylene chloride,the extract dried over MgSO₄ and the solvent evaporated, yielding a tansolid. The crude product was dissolved in benzene and allowed tocrystallize giving a white solid; a second crop was obtained by additionof n-hexane, yielding a total of 1.1 g of3-fluoro-8-chloro-5-(2-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one:mp 204°-205°; ¹ H nmr (DMSO-d₆) δ 7.6 ppm (m, 6 H), δ 7.0 ppm (m, 1H), δ5.94 ppm (d, 56 Hz, 1H), δ 3.45 ppm (s, 3H); ¹⁹ F nmr (DMSO-d₆) δ -161.8ppm (d, J = 56 Hz).

Anal. Calcd for C₁₆ H₁₁ N₂ OCl₂ F: C, 56.99; H, 3.29; N, 8.31; Cl,21.03; F, 5.63. Found: C, 57.11; H, 3.54; N, 8.37; Cl, 20.84; F, 5.69.

EXAMPLE 133-Fluoro-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one##STR17##

A well stirred suspension of 3.6 g (0.012 mole) of1,3-dihydro-3-hydroxy-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one in 200ml methylene chloride was cooled to -70°, and 5 ml (0.04 mole) ofdiethylaminosulfur trifluoride was added dropwise. The reaction mixturewas allowed to warm slowly to -10°, at which temperature all of thesolid went into solution. The reaction mixture was poured into 400 ml ofice water, and the organic layer was separated, washed with water, dried(MgSO₄) and evaporated to dryness under reduced pressure. The residuewas recrystallized from benzene-heptane to give 3.0 g (83%) of3-fluoro-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one ascolorless crystals: mp 174°-175° (dec.); ¹ H nmr (DMSO-d₆) δ 5.90 ppm(d, J = 57 Hz, 1H), 7.3-7.7 ppm (m, 6H), 8.07 ppm (d, J = 2.5 Hz, 1H)and 8.45 ppm (d, d, J = 9.0, 2.5 Hz, 1H); ¹⁹ F nmr (DMSO-d₆) δ -161.4ppm (d, J = 57 Hz).

Anal. Calcd for C₁₅ H₁₀ FN₃ O₃ : C, 60.20; H, 3.37; F, 6.35; N, 14.04.Found: C, 60.02; H, 3.43; F, 6.21; N, 13.88.

EXAMPLE 143-Fluoro-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one##STR18##

A slurry of 0.20 g (0.08 mole) of sodium hydride in 10 ml oftetrahydrofuran was added to a solution of 1.74 g (0.0058 mole) of3-fluoro-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one and 10ml methyl iodide in 100 ml of tetrahydrofuran at 25°. The reactionmixture was stirred for 3 hr at 25°, and then poured into 300 ml of icewater. The aqueous mixture was extracted with methylene chloride, andthe extracts were dried (MgSO₄) and then evaporated to dryness underreduced pressure. The residue was dissolved in hot benzene and thenfractionally precipitated by the addition of hexane. The first darkfractions of solid were discarded. The remaining fractions werecollected on a filter and dried in vacuum to give 1.10 g (60%) of3-fluoro-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-oneas a light tan amorphous solid with no distinct melting point: ¹ H nmr(CDCl₃) δ 3.53 ppm (s, 3H), 5.59 ppm (d, J = 57 Hz, 1H), 7.2-7.9 ppm (m,6H) and 8.2-8.9 ppm (m, 2H); ¹⁹ F nmr (CDCl₃) δ -161.7 ppm (d, J = 57Hz).

EXAMPLE 153-Fluoro-7-chloro-1,3-dihydro-N-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-1-carboxamide##STR19##

A stirred mixture of 3.56 g (0.12 mol) of3-fluoro-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 35 mlof benzene and 1.06 g (0.019 mol) of methyl isocyanate was refluxedslowly for approximately 20 hours. The cool mixture was evaporated todryness under reduced pressure to give 4.42 g of crude product as alight beige powder. Recrystallization from approximately 100 ml of hotethanol gave 1.99 g of a white powder (mp 224°-225°) identified as3-fluoro-7-chloro-1,3-dihydro-N-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-1-carboxamide:¹ H nmr (CDCl₃) δ 8.4-8.7 ppm (1H, N--H, broad quartet); δ 7.25-8.0 (8H,m, aromatic); δ 5.72 (1H, d, J = 56.5 Hz); δ 2.93 (3H, d, J = 4.5 Hz,N--CH₃). ¹⁹ F nmr (CDCl.sub. 3) δ -160.75 ppm (J = 57 Hz).

Anal. Calcd for C₁₇ H₁₃ N₃ ClO₂ F: C, 59.05; H, 3.79; N, 12.15; F, 5.49.Found: C, 59.01; H, 4.00; N, 11.69; F, 5.28.

EXAMPLE 163-Fluoro-7-chloro-1,3-dihydro-N-ethyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-1-carboxamide##STR20##

A stirred mixture of 3.56 g (.012 mol) of3-fluoro-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 35 mlof benzene and 1.29 g (0.018 mol) of ethylisocyanate was refluxed slowlyfor about 20 hours. A suspended insoluble solid was removed from thecool mixture by filtration. The filtrate was then evaporated to drynessunder reduced pressure to give 1.92 g of a yellow glassy material.Recrystallization from approximately 100 ml of cyclohexane gave 0.90 gof an off-white powder (mp 110°-112°) identified as3-fluoro-7-chloro-1,3-dihydro-N-ethyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-1-carboxamide:¹ H nmr (CDCl₃): δ 1.2 ppm (t, 3H, J = 7 Hz), δ 3.1-3.68 (dg, 2H), δ5.67 (d, 1H, J = 57 Hz), δ 7.2-8.0 (aromatic), δ 8.7 (N--H). ¹⁹ F nmr(CDCl₃): δ -160.67 ppm (d, J = 57 Hz).

EXAMPLE 174-Fluoro-8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4.3-a]-[1.4]benzodiazepin##STR21##

A solution of 5.0 g (0.014 mole) of8-chloro-4-hydroxy-1-methyl-4H-s-triazolo[4.3-a][1,4]benzodiazepinemethanol solvate in 250 ml methylene chloride was cooled to -70°, and 10ml of diethylaminosulfur trifluoride was added over a period of 10 min.The reaction mixture was warmed over 20 min. to -20°, held at -20° for20 min., and then poured into 500 ml of ice water. The aqueous mixturewas neutralized with sodium bicarbonate, and the organic layer wasseparated, washed with water, dried (MgSO₄), and evaporated to drynessto give 4.1 g of4-fluoro-8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4.3-a]-[1,4]-benzodiazepine:mp 232°-235° (dec.); ¹⁹ F nmr (DMSO-d₆) δ -167.1 ppm (d, J = 52 Hz); ¹ Hnmr (DMSO-d₆) δ 2.62 ppm (s, 3H), 6.71 ppm (d, J = 52 Hz, 1H), 7.3-8.1ppm (m, 8H).

The 4-hydroxy compound used in this preparation can be prepared asdescribed in U.S. Pat. No. 3,907,820 (1975) (assigned to Takeda ChemicalIndustries, Ltd.).

Table 1 shows additional compounds that can be made using theappropriate 3-hydroxy starting material in the general method.

                                      Table 1                                     __________________________________________________________________________    3-Hydroxybenzo-    Dialkylamino-                                                                          3-Fluorobenzo-                                    diazepinone        sulfur Trifluoride                                                                     diazepinone                                       __________________________________________________________________________     ##STR22##         (C.sub.2 H.sub.5).sub.2 NSF.sub.3                                                       ##STR23##                                         ##STR24##         (C.sub.2 H.sub.5).sub.2 NSF.sub.3                                                       ##STR25##                                         ##STR26##                                                                                        ##STR27##                                                                              ##STR28##                                         ##STR29##         (C.sub.2 H.sub.5).sub.2 NSF.sub.3                                                       ##STR30##                                         ##STR31##                                                                                        ##STR32##                                                                              ##STR33##                                         ##STR34##         (C.sub.2 H.sub.5).sub.2 NSF.sub.3                                                       ##STR35##                                         ##STR36##         (CH.sub.3).sub.2 NSF.sub.3                                                              ##STR37##                                         ##STR38##         (C.sub.2 H.sub.5).sub.2 NSF.sub.3                                                       ##STR39##                                        __________________________________________________________________________

table 2 shows additional compounds that can be made by the alternatemethod using the appropriate fluorobenzodiazepinone.

                                      Table 2                                     __________________________________________________________________________    1-Unsubstituted                                                                              Alkylating                                                                              1-Substituted                                        Benzodiazepinone                                                                             Reagent   Benzodiazepinone                                     __________________________________________________________________________     ##STR40##     BrCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                    ##STR41##                                            ##STR42##     CF.sub.3 CH.sub.2 OSO.sub.2 CF.sub.3                                                     ##STR43##                                            ##STR44##     ClCH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2                                             ##STR45##                                            ##STR46##     CH.sub.3 I                                                                               ##STR47##                                            ##STR48##                                                                                    ##STR49##                                                                               ##STR50##                                            ##STR51##                                                                                    ##STR52##                                                                               ##STR53##                                           __________________________________________________________________________

table 3 shows additional 4-fluorotriazolobenzodiazepines that can bemade using the appropriate 4-hydroxy starting material.

                  TABLE 3                                                         ______________________________________                                        4-Hydroxytriazolo-                                                                        Dialkylamino- 4-Fluorotriazolo-                                   benzodiazepine                                                                            Sulfur Trifluoride                                                                          benzodiazepine                                      ______________________________________                                         ##STR54##                                                                     ##STR55##                                                                     ##STR56##                                                                    ______________________________________                                    

dosage Forms

The tranquilizers, muscle relaxants, and sedatives of this invention canbe administered to produce the desired effect by any means that producescontact of the active agent with the agent's site of action in the bodyof a mammal. They can be administered by any conventional meansavailable for use in conjunction with pharmaceuticals; either asindividual therapeutic agents or in a combination of therapeutic agents.They can be administered alone, but are generally administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon knownfactors such as the pharmacodynamic characteristics of the particularagent, and its mode and route of administration; age, health, and weightof the recipient; nature and extent of symptoms, kind of concurrenttreatment, frequency of treatment, and the effect desired. Usually adaily dosage of active ingredient can be about 0.001 to 100 milligramsper kilogram of body weight. Ordinarily 0.01 to 50, and preferably 0.05to 25 milligrams per kilogram per day given in divided doses 2 to 4times a day or in sustained release form is effective to obtain desiredresults.

Dosage forms (compositions) suitable for internal administration containfrom about 0.1 milligrams to about 500 milligrams of active ingredientper unit. In these pharmaceutical compositions the active ingredientwill ordinarily be present in an amount of about 0.5-95% by weight basedon the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions; it can also be administeredparenterally, in sterile liquid dosage forms; or rectally in the form ofsuppositories.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, sucrose, mannitol, starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of hours. Compressed tablets can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration contain preferably a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid either alone or combined aresuitable stabilizing agents. Also used are citric acid and its salts andsodium EDTA. In addition parenteral solutions can contain preservatives,such as benzalkonium chloride, methyl- or propyl-paraben, andchlorobutanol.

Suppositories contain the active ingredient in a suitable oleaginous orwater-soluble base. The oleaginous class includes cocoa butter and fatswith similar properties; and water-soluble class includes polyethyleneglycols.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, E. W. Martin, a standard reference text in thisfield.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 2.0 milligrams of powderedactive ingredient, 110 milligrams of lactose, 32 milligrams of talc, and8 milligrams magnesium stearate.

Capsules

A mixture of active ingredient in soybean oil is prepared and injectedby means of a positive displacement pump into gelatin to form softgelatin capsules containing 1 milligram of the active ingredient. Thecapsules are washed in petroleum ether and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 0.5 milligrams of active ingredient, 7milligrams of ethyl cellulose, 0.2 milligrams of colloidal silicondioxide, 7 milligrams of magnesium stearate, 11 milligrams ofmicrocrystalline cellulose, 11 milligrams of cornstarch and 98.8milligrams of lactose. Appropriate coatings may be applied to increasepalatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is sterilized byfiltration.

Suspension

An aqueous suspension is prepared for oral administration so that each 5milliliters contain 0.5 milligrams of finely divided active ingredient,500 milligrams of acacia, 5 milligrams of sodium benzoate, 1.0 grams ofsorbitol solution, U.S.P., 5 milligrams of sodium saccharin, and 0.025milliliters of vanilla tincture.

Injectable

A parenteral composition suitable for administration by injection isprepared by dissolving 1% by weight of active ingredient in sodiumchloride injection U.S.P. XV and adjusting the pH of the solution tobetween 6 and 7. The solution is sterilized by filtration.

Utility

Standard procedures for detecting and comparing the tranquilizer,muscle-relaxant, and sedative activity of compounds in this series forwhich there is a correlation with human efficacy are the following:pinna reflex tests, antipentylenetetrazole test, rat activitysuppression test (RAST), muscle relaxant (anti-straub tail) test, andmouse activity suppression test (MAST).

PINNA REFLEX TESTS

Fasted female white mice, 5 per dose are intubated with drug at 4, 12,36, 108 and 324 mg/kg in 1% Methocel®- 1.25% Tween 80®, at 10 ml/kg. Theauditory and tactile pinna are tested at 0.5, 2, 5 and 24 hours.

Auditory Pinna Reflex

The mouse is placed on a horizontal bar 9 cm from a Galton whistleadjusted for 13 Kc. Failure to flatten the ears during one or 2 shortbursts of sound constitutes loss of auditory pinna reflex.

Tactile Pinna Reflex

The mouse is held by the tail and the hairs inside the right ear aretouched by the fine wire stylus from a 27 gauge needle. Failure of themouse to twitch or move the head constitutes loss of the tactile pinnareflex.

ANTIPENTYLENETETRAZOLE (PTZ) TEST

Fasted female white mice, 10 per dose are intubated with drug in vehicleas above at doses such as 0, 1, 3, 9, 27 and 81 mg/kg. Thirty minuteslater the mice are dosed intravenously with PTZ (Metrazol®¹) at 40 mg/kg(ED98 for clonic convulsions). Dosed animals which remain on a 4" × 4"platform for 20 seconds are considered protected. Quantal ED₅₀ 's arecalculated by the moving average method.

RAT ACTIVITY SUPPRESSION TEST (RAST)

The test apparatus consists of a circular cage with lid and with a floorof electrifiable steel bars. D.C. shock current is supplied to the barssuch that touching any 2 alternate bars shocks the rat. The floor ismarked to yield 4 equal pie-shaped sectors.

Fasted male white rats, 10 per dose are intubated with drug as describedabove for mice. Thirty minutes after dosing a rat is placed in the testapparatus and is allowed 30 seconds to transverse 25% of the floor areaafter which he receives a shock. The rat is allowed 5 seconds to recoverfrom the shock, then its "line crossings" are counted for 60 seconds.The mean number of crossings per rat for each dose are determined andare compared to the mean number of crossings of the vehicle treatedcontrols. ED₅₀ %, the dose which would increase the number of crossings50% over controls, is determined graphically.

MUSCLE RELAXANT (ANTI-STRAUB TAIL) TEST

Fasted female white mice, 5 per dose are intubated with test drug.Twenty-five minutes later morphine sulfate is given subcutaneously at53.7 mg/kg. Thirty minutes after test drug the mice are observed forpresence of Straub tail. Quantal ED₅₀ values for blockade ofmorphine-induced Straub tail are calculated.

MOUSE ACTIVITY SUPPRESSION TEST (MAST)

The Mouse Activity Suppression Test (MAST) is a model system designed todetect compounds with possible anti-anxiety activity in humans. The testis based upon punishment of mice for exhibiting normal exploratorylocomotor behavior. The punishment, an electric shock applied throughthe mouse's paws, quickly extinguishes normal behavior. Pretreatmentwith a minor tranquilizer prevents or delays the extinction, while majortranquilizers, analgesics, stimulants, anti-depressants,antihistaminics, and purely sedative drugs are inactive.

The test procedure is modified from Boissier, et al., European J.Pharm., 4, 145-151 (1968). Female white mice, fasted 16-22 hours, arerandomly distributed to fiberglass holding boxes. Mice in groups of10-20 are dosed orally and returned to their holding boxes until testtime. Test drug suspensions or solutions are prepared by sonication in1% Methocel®. Typical dose ranges include 0.5, 1, 2, and 4 mg/kg or 1,3, 9, 27, 81 mg/kg plus a vehicle control and are selected to includeone dose at which an effect such as sedation, stimulation, muscleweakness or analgesia was seen.

The test apparatus is an opaque, black plastic box with a clear lid anda stainless steel grid floor. The floor of the test box is marked offinto four squares of equal size.

After dosing, a mouse is gently place in one corner of the testing boxand during the next minute each time the mouse makes a full crossingfrom one square section of the box to another the floor is electrifiedwith 0.4 ma current for 2.0 seconds.

The number of shocks received by each mouse is recorded and the meannumber of shocks/dose (X) is determined. When X drug at any dose isstatistically greater than X controls (Student's t test), antagonism ofsuppression obtains and the drug is presumed to have anti-anxietyactivity.

Potency in the antipentylenetetrazole (PTZ), the MAST, and the RASTtests indicates a potent antianxiety agent. Great potency for blockadeof the mouse auditory pinna reflex with little or no effect on tactilepinna reflex is characteristic of minor tranquilizers. Potency in themouse anti-straub tail test suggests skeletal muscle relaxant activity.

The following table includes the results of these tests conducted with arepresentative sample of the compounds of this invention; it alsoincludes the results for diazepam, oxazepam, and chlordiazepoxide, threewell-known benzodiazepines widely-used commercially as tranquilizers.

    __________________________________________________________________________     ##STR57##                                                                                           MOUSE ED50 VALUES                                                             PINNA REFLUX                                                                            ANTI-    MUSCLE  RAT ED50% VALUES            Compound   X Y Z       Auditory                                                                           Tactile                                                                            PTZ MAST*                                                                              RELAXANT                                                                              RAST                        __________________________________________________________________________    Diazepam.sup.a                                                                           Cl                                                                              H CH.sub.3                                                                              4    187  0.49                                                                              1.1  1       1.5                         Oxazepam.sup.b                                                                           Cl                                                                              H H       2.9       2.  2.7  0.26    2.5                         Chlordiazepoxide.sup.c                                                                   Cl                                                                              H H       70   320  7.5 8.5  1.9     6.                                     Cl                                                                              H H       2.6       0.39                                                                              0.37.sup.d                                                                         0.10                                           Cl                                                                              F H       12   200  0.42                                                                              0.48 --                                             Cl                                                                              Cl                                                                              H       < 4  >324 0.34                                                                              1.15 <0.33                                          Cl                                                                              H CH.sub. 3                                                                             5    121  0.18                                                                              0.25 0.25    0.45                                   Cl                                                                              F CH.sub.3                                                                              7    200  0.12                                                                              0.05 0.06    0.24                                   Cl                                                                              Cl                                                                              CH.sub.3                                                                              60   >324 0.09                                                    Cl                                                                              H C.sub.2 H.sub.5                                                                       12   >324 0.56                                                                              0.45 <0.24                                          Cl                                                                              H CH.sub.2 CHCH.sub.2                                                                   20   100  6.1 2.9  <1                                             Cl                                                                              H                                                                                ##STR58##                                                                            <4    36                                                          Br                                                                              H H       1.2  100  0.74                                                                              0.04 0.05    0.15                                   Br                                                                              F H       < 4  300  0.12                                                    Br                                                                              H CH.sub.3                                                                              1.3  300  0.22                                                                              0.16         1.7                                    Br                                                                              F CH.sub.3                                                                              < 4  <324 0.06                                         __________________________________________________________________________     .sup.a 3F replaced by 3H.                                                     .sup.b 3F replaced by 30H.                                                    .sup.c No 3F, carbonyl replaced by NHCH.sub.3 and → 0 on the 4N.       .sup.d At 60 minutes; all others were at 30 minutes.                          *ED20%                                                                   

We claim:
 1. A Process for preparing a compound of the formula:##STR59## wherein X is Cl, Br, NO₂ or CF₃ ;Y is H, Cl, Br or F; Z is H,hydrocarbyl of 1-4 carbons, --CH₂ --CF₃, --COHNR, --CH₂ --CH₂ NR₂ or--CH₂ CH₂ NR₂.A, where R is alkyl of 1-4 carbons, and A is apharmaceutically suitable acid; B is O; or B and Z together is═N--N═C(R')-where R' is H or C₁ -C₄ alkylwhich comprises: contacting,under substantially anhydrous conditions at a temperature of about -80°to +10° C., a compound of the formula ##STR60## with a compound of theformula: ##STR61## where B, X, Y and Z are as previously defined, and R¹and R² individually are a primary alkyl group of 1-4 carbons or takentogether are --(CH₂)₄ -- or --(CH₂)₅ --.